ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2172_2173delinsAG (p.Arg725Gly) (rs786203433)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166735 SCV000217546 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000463195 SCV000543545 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-01 criteria provided, single submitter clinical testing This is a complex sequence change that replaces arginine with glycine at codon 725 of the MLH1 protein (p.Arg725Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (rs786203433, ExAC no frequency). While this variant has not been reported in the literature in individuals with an MLH1-related disease, a different sequence change, c.2173C>G, that results in the same amino acid substitution (p.Arg725Gly), was reported in an individual affected with breast cancer (PMID: 25503501). Segregation studies were not performed and the clinical significance of this finding was not determined. ClinVar contains an entry for this variant (Variation ID: 187049) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480782 SCV000568075 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2172_2173delGCinsAG at the cDNA level, p.Arg725Gly (R725G) at the protein level. The surrounding sequence is CCTT[delGC][insAG]GCTC. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of an Arginine to a Glycine (CGC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither MLH1 c.2172_2173delGCinsAG nor MLH1 Arg725Gly were observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg725Gly occurs at a position that is conserved across species and is located in the region known to interact with PMS2, MLH3, and PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg725Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166735 SCV001346740 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-21 criteria provided, single submitter clinical testing

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